Leber hereditary optic neuropathy

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Leber hereditary optic neuropathy (LHON) is an inherited form of vision loss. Although this condition usually begins in a person's teens or twenties, rare cases may appear in early childhood or later in adulthood. For unknown reasons, males are affected much more often than females.

Blurring and clouding of vision are usually the first symptoms of LHON. These vision problems may begin in one eye or simultaneously in both eyes; if vision loss starts in one eye, the other eye is usually affected within several weeks or months. Over time, vision in both eyes worsens with a severe loss of sharpness (visual acuity) and color vision. This condition mainly affects central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. Vision loss results from the death of cells in the nerve that relays visual information from the eyes to the brain (the optic nerve). Although central vision gradually improves in a small percentage of cases, in most cases the vision loss is profound and permanent.

Vision loss is typically the only symptom of LHON; however, some families with additional signs and symptoms have been reported. In these individuals, the condition is described as "LHON plus." In addition to vision loss, the features of LHON plus can include movement disorders, tremors, and abnormalities of the electrical signals that control the heartbeat (cardiac conduction defects). Some affected individuals develop features similar to multiple sclerosis, which is a chronic disorder characterized by muscle weakness, poor coordination, numbness, and a variety of other health problems.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Mutations in the MT-ND1, MT-ND4, MT-ND4L, or MT-ND6 gene can cause LHON. These genes are found in the DNA of cellular structures called mitochondria, which convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA, known as mitochondrial DNA or mtDNA.

The genes associated with LHON each provide instructions for making a protein involved in normal mitochondrial function. These proteins are part of a large enzyme complex in mitochondria that helps convert oxygen, fats, and simple sugars to energy. Mutations in any of the genes disrupt this process. It remains unclear how these genetic changes cause the death of cells in the optic nerve and lead to the specific features of LHON.

A significant percentage of people with a mutation that causes LHON do not develop any features of the disorder. Specifically, more than 50 percent of males with a mutation and more than 85 percent of females with a mutation never experience vision loss or related health problems. Additional factors may determine whether a person develops the signs and symptoms of this disorder. Environmental factors such as smoking and alcohol use may be involved, although studies have produced conflicting results. Researchers are also investigating whether changes in additional genes contribute to the development of signs and symptoms.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

LHON has a mitochondrial pattern of inheritance, which is also known as maternal inheritance. This pattern of inheritance applies to genes contained in mtDNA. Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, children can only inherit disorders resulting from mtDNA mutations from their mother. These disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass traits associated with changes in mtDNA to their children.

Often, people who develop the features of LHON have no family history of the condition. Because a person may carry an mtDNA mutation without experiencing any signs or symptoms, it is hard to predict which members of a family who carry a mutation will eventually develop vision loss or other problems associated with LHON. It is important to note that all females with an mtDNA mutation, even those who do not have any signs or symptoms, will pass the genetic change to their children.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

The prevalence of LHON in most populations is unknown. It affects 1 in 30,000 to 50,000 people in northeast England and Finland.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Mitochondrial respiratory chain defects · Very frequent (99-80%)

Slow decrease in visual acuity · Very frequent (99-80%)

Blurred vision · Frequent (79-30%)

Lack of sharpness of vision resulting in the inability to see fine detail.

Central scotoma · Frequent (79-30%)

An area of depressed vision located at the point of fixation and that interferes with central vision.

Centrocecal scotoma · Frequent (79-30%)

A scotoma (area of diminished vision within the visual field) located between the central point of fixation and the blind spot with a roughly horizontal oval shape.

Optic atrophy · Frequent (79-30%)

Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.

Progressive visual loss · Frequent (79-30%)

A reduction of previously attained ability to see.

Retinal telangiectasia · Frequent (79-30%)

Localized, irregular dilatation of small tortuous intraretinal blood vessels.

Other findings in the same source

From: Orphanet

Additional reported features include Retinal vascular tortuosity (Frequent (79-30%)); Abnormal electroretinogram (Occasional (29-5%)); Abnormality of visual evoked potentials (Occasional (29-5%)); Arrhythmia (Occasional (29-5%)); Ataxia (Occasional (29-5%)); Color vision defect (Occasional (29-5%)); Myopathy (Occasional (29-5%)); Peripheral neuropathy (Occasional (29-5%)); Postural tremor (Occasional (29-5%)); Reduced contrast sensitivity (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Leber hereditary optic neuropathy is Ophthalmology, with a ophthalmologist as the relevant type of clinician. Ophthalmologist; paediatric services for children as appropriate.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which part of the eye or visual pathway is affected?
• What change in vision requires immediate contact with the eye service?
• What are the aims and alternatives of any proposed eye treatment?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Leber hereditary optic neuropathy. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.